Abstract Squamous cell carcinoma of the head and neck (SCCHN) remains one of the deadliest cancers in the United States. Despite many emerging new treatments there has been almost no success in improving either the morbidity or mortality of this disease. Continuing advances in immunology make immunotherapy an active area for current and future cancer research. However, the design of immunotherapeutic strategies for SCCHN requires an understanding of the tumor microenvironment. We have recently observed that a senescence-like process is involved in the dysfunction of T lymphocytes in the tumor microenvironment. Further, these cells not only have senescent features, but in addition have functional changes consistent with suppressor cells. Future success of immunotherapeutic approaches for cancer patients are dependent on the protection of T cells from such changes at the tumor site and the enhancement of their efficiency. Mcl-1, a prosurvival Bcl-2 family member, has recently been demonstrated to be required for the survival of mature T lymphocytes. Our preliminary results suggest that Mcl-1 may have a key regulatory role in the protection of T lymphocytes from tumor-induced senescence that is mediated through the pro-senescent and -apoptotic molecule, p53. Noteworthy, among the pro-survival Bcl-2 family members, Mcl-1 is the major protein to undergo significant upregulated expression in response to cytokines used for immunotherapy, such as, IL-2, IL-7, and IL-12. The current application will attempt to elucidate the role and functional mechanisms of Mcl-1 in the protection of SCCHN-associated lymphocytes from senescence at the tumor microenvironment. The underlying scientific approach will employ a model of tumor-induced senescence of T cells to further characterize the mechanisms involved in this process with an emphasis on the regulation of p53 senescent activity by Mcl-1. Further characterization of the suppressor function of these senescent T cells will be performed to better understand the impact of this process on the immune system. The translational components of this proposal will evaluate the diagnostic potential of the newly identified senescent suppressor T cells and elucidate intracellular targets for the improvement of current immunotherapeutic protocols for SCCHN. Project Narrative The goal of the current project is to elucidate a new form of tumor immune evasion. By gaining a better understanding of the molecular mechanisms involved in the formation of cancer associated dysfunctional T cells new diagnostic and therapeutic regimens can be devised. The proposal centers on explaining how cancer in part evades the immune system through directly altering T cells with the goal of improving the success of emerging immune based therapies.